PI3K Inhibitor Shows Promise in Early Trial

A key player in metabolism, division, and other cellular functions, the phosphoinositide 3-kinase (PI3K) pathway is often mutated in tumors. A drug that targets a highly common PI3K mutation has shown positive results in a first-in-humans phase I trial, according to findings presented this week at the American Association for Cancer Research Annual Meeting 2013 in Washington, DC, April 6-10.

Alterations in the PI3K pathway frequently show up in breast, brain, lung, and colon tumors, and in other cancer types. For example, oncogenic activation of this pathway in HER2-positive breast cancer has been associated with resistance to trastuzumab (Herceptin; Genentech).

Mutations to PIK3CA, which encodes the alpha subunit of the PI3K catalytic subunit, are estimated to be present in approximately 40% of hormone receptor-positive breast cancers.

So far, no drugs aimed specifically at cancers with PIK3CA mutations have been approved by the U.S. Food and Drug Administration. One PI3K alpha-isoform-specific inhibitor that has reached phase I trials, however, is Genentech's GDC-0032.

Dejan Juric, MD, of the Massachusetts General Hospital Cancer Center in Boston, MA, and colleagues conducted a phase Ia dose-escalation trial of GDC-0032 on 34 patients who had metastatic or locally advanced solid tumors. The patients received doses of the drug ranging from 3 mg per day to 16 mg per day. Side effects included diarrhea, nausea, and fatigue, with the most serious being hyperglycemia in 2 patients receiving the highest dose. “In general, hyperglycemia is very manageable with treatment with standard therapeutics,” such as metformin, says Juric.

The researchers gauged the drug's effectiveness by using FDG-PET to monitor the tumors' absorption of glucose. More than half of the patients the team tested showed at least a 20% reduction in glucose uptake, suggesting that the drug was inhibiting the PI3K pathway.

Juric and colleagues also confirmed that tumors had shrunk in 6 of the patients, 4 of whom had breast cancer with PIK3CA mutations. “What is unique is that the drug is very potent, and it's selective for cancers that have PIK3CA mutations,” says Juric.